Estrogens are prothrombotic. Recently, the Heart and Estrogen/progestin Replacement Study (HERS), renewed interest in the adverse effects of hormone replacement therapy (HRT). In HERS, HRT was no better than placebo at preventing coronary events. In post hoc analyses, treatment was associated with early harm and late benefit. In an AHA-funded case-control study, we identified a potential interaction between HRT and the prothrombin G20210A variant on the risk of first myocardial infarction (MI) in post-menopausal women with hypertension. Aims: The primary purpose is to examine the potential interactions of hormone replacement therapy with other procoagulant variants on the risk of cardiovascular events, and the main variants of interest are: (la) factor XIIIA Val34Leu; (ib) platelet glycoprotein (PGP) Jib Ile843Ser; (ic) PGP IIIa Leu33Pro; and (id) PGP Ia C807T. The secondary aims include the assessment of other drug-gene, risk-factor-gene or gene-gene interactions on risk: (2a) the interaction between PGP IIb Ser843, PGP lila Leu33Pro and PGP Ia C807T and traditional cardiovascular risk factors such as smoking and obesity on the risk of MI and stroke; (2b) the interaction between three coagulation factor XIII polymorphisms and PAl-1 4G/5G on the risk of stroke in women; and (2c) the interaction between aspirin use and glycoprotein IIIa Leu33Pro on the risk of MI and stroke. Methods: The setting is Group Health Cooperative (GHC). GHC computerized files will be used to identify postmenopausal females, aged 30 to 79 yrs, with incident MI or stroke during 1/2000-12/2004. Population-based controls, sampled from the GHC enrollment files, will be frequency matched to cases by age, calendar year, and treated hypertension. Data collection will include medical-record review, telephone interview of consenting subjects, and venous-blood collection. Standard methods will be used to assay variant alleles. The GHC computerized pharmacy records will serve as the primary source of information about the use of HRT. Data analysis will involve restriction, stratification, and logistic regression. Case-control and case-only analyses are planned. By including subjects recruited in previous and on-going studies, the proposed project will also enable us to test new hypotheses efficiently in a total of 600 MI cases, 420 stroke cases and 1800 controls. Power for primary and secondary aims is excellent. Information from this project may help physicians counsel women about HRT to maximize either effectiveness, or safety, or both.